Humanizing mismatch repair in yeast: towards effective identification of hereditary non-polyposis colorectal cancer alleles

The correction of replication errors is an essential component of genetic stability. This is clearly demonstrated in humans by the observation that mutations in mismatch repair genes lead to HNPCC (hereditary nonpolyposis colorectal cancer). This disease accounts for as many as 2-3% of colon cancers. of these, most of them are in the two central components of mismatch repair, MLH1 (mutL homologue 1) and MSH2 (MutS homologue 2). MLH1 and MSH2 function as a complex with two other genes PMS2 and MSH6. Mismatch repair genes, and the mechanism that ensures that incorrectly paired bases are removed, are conserved from prokaryotes to human. Thus yeast can serve as a model organism for analysing mutations/polymorphisms found in human mismatch repair genes for their effect on post-replicative repair. To date, this has predominantly been accomplished by making the analogous mutations in yeast genes. However, this approach is only useful for the most highly conserved regions. Here, we discuss some of the benefits and technical difficulties involved in expressing human genes in yeast. Modelling human mismatch repair in yeast will allow the assessment of any functional effect of novel polymorphisms found in patients diagnosed with colon cancers.